Among the many disorders resulting in osteoarthritis, there are several forms that are clearly genetic in origin. These diseases are inherited as dominant traits in a Mendelian pattern, and there is no evidence that any environmental factor plays a major role in etiology. The most common of the inherited OA disorders is primary generalized osteoarthritis (PGOA), characterized by early-onset degeneration of multiple joints, particularly the hips and knees, and the appearance of Heberden's nodes in the distal phalangeal joints. The second type of inherited OA is chondrocalcinosis (CC) resulting from deposits of calcium phosphate dihydrate in the joints. The third familial OA is Wagner-Stickler syndrome, or arthro-ophthalmopathy (AO), the symptoms of which include retinopathy in addition to the degenerative joint disease. The objective of this research is to identify the genes at fault in these disorders through genetic linkage analysis. Restriction fragment length polymorphisms (RFLPs) will be used to test genes expressed in cartilage and other candidate chromosomal loci for genetic linkage to inherited OA. The results will conclusively rule out some genes as the site of the primary defect and strongly implicate others that show close genetic linkage. These studies will begin with genes for major cartilage proteins (such as type II and type VI procollagen). Forms of inherited OA not linked to any of the candidate cartilage genes will be mapped by linkage to one or more of the many highly polymorphic anonymous RFLPs now available for human chromosome mapping. Genetic mapping of OA in various families will establish the extent of genetic heterogeneity of these diseases, i.e. whether different genes are at fault in different families. The ultimate objective in identifying the genes responsible for inherited forms of OA is to understand the molecular basis of these diseases, so that more effective prevention and treatment might be developed. The gene products and the pathways leading to joint degeneration in familial OA would also become rational starting points for studying the molecular basis of other forms of OA.